Increased mortality, blunted production of nitric oxide, and increased production of TNF-alpha in endotoxemic TGF-beta1 transgenic mice.
The expression of the inducible isoform of nitric oxide synthase (NOS2, iNOS) is increased in patients undergoing sepsis as well as in animal models in which septic shock is induced by injection of bacterial lipopolysaccharide (LPS). Transforming growth factor-beta1 (TGF-beta1) potently suppresses NO production both in vitro and in vivo. After intraperitoneal injection of LPS, mice over-expressing a cDNA coding for active TGF-beta1 in the liver (Alb/ TGF-beta1) exhibited reduced serum levels of the NO reaction products NO2(-) + NO3(-) compared with controls. Paradoxically, while endotoxemic Alb/ TGF-beta1 mice expressed much less NOS2 protein in peritoneal exudate cells than did endotoxemic wild-type mice, Alb/TGF-beta1 mice expressed more NOS2 mRNA and protein in both liver and kidney. Alb/ TGF-beta1 mice treated with LPS had eightfold higher serum tumor necrosis factor alpha (TNF-alpha) levels and experienced increased mortality compared with wild-type mice, which was associated with renal insufficiency. These results suggest that renal dysfunction, decreased production of NO, and/or increased production of TNF-alpha are associated with increased mortality of endotoxemic Alb/TGF-beta1 mice.
Vodovotz
Y
Y
Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. yxv1@mhg.edu
Kopp
J B
JB
Takeguchi
H
H
Shrivastav
S
S
Coffin
D
D
Lucia
M S
MS
Mitchell
J B
JB
Webber
R
R
Letterio
J
J
Wink
D
D
Roberts
A B
AB
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002448:Cell Adhesion / Q000187:drug effects; D004487:Edema / Q000139:chemically induced; D019446:Endotoxemia / Q000401:mortality / Q000503:physiopathology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007674:Kidney Diseases / Q000150:complications; D008099:Liver / Q000098:blood supply; D051379:Mice; D008822:Mice, Transgenic; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase